The behavioral changes produced by amphetamine and related CNS stimulants (methylphenidate and pipadrol) are thought to be mediated through the release of dopamine (DA) from specific sites in the brain. This suggests that amphetamine can increase the rate of DA turnover. We propose to study the mechanism of the stimulation of DA turnover using striatal slices. Amphetamine can stimulate the synthesis and release of Da in this preparation at low concentrations, both effects are enhanced by the addition of calcium. Consequently, we will try to determine 1) the nature of the amphetamine-calcium interaction; 2) how this interaction leads to the stimulation of tyrosine hydroxylase activity; and 3) the role of calcium in the amphetamine-induced release of DA. Since the effects of amphetamine on tyrosine hydroxylase activity in striatal slices appears to be similar to that of depolarizing agents, we will compare the effects of amphetamine with veratridine and high potassium concentration on the activity of the enzyme in this preparation. We will also characterize the effects of methylphenidate and pipadrol on DA synthesis and release. We also intend to study the role of DA synthesis and the transport of amphetamine into DA neurons on the amphetamine-induced stimulation on locomotor activity and circling behavior. Finally we will determine the interaction between GABA and amphetamine in producing these behavioral effects. These studies will be of value in defining the molecular mechanisms involved in the behavioral effects of amphetamine and analogous CNS stimulants and in understanding how the balance between the synthesis and release of neurotransmitters is maintained under normal and pathological conditions.